Patients suffering from malignant hematological disorders such as leukemia or lymphoma may, under appropriate circumstances, be administered autologous or allogeneic bone marrow transplants as part of a therapeutic regimen. Such transplants also can be useful in conjunction with therapy of non-hematological malignancies such as breast carcinomas or other solid tumors. Bone marrow transplantation makes it possible to administer to patients with resistant disease high, "supra-lethal," combinations of chemotherapy and/or radiation, ignoring the irreversible toxicity of such therapeutic combinations on the normal bone marrow compartment. Nevertheless, such "debulking" of a patient's tumor can leave a fraction of residual malignant cells that may lead to disease relapse.
Several lines of evidence suggest that a significant proportion of the beneficial effect of allogeneic bone marrow transplantation (i.e., bone marrow transplantation from an individual not genetically identical to the host patient) stems from cell-mediated interactions of immune cells of donor origin against residual tumor cells in the host that have escaped the chemoradiotherapy debulking regimen. Following allogeneic bone marrow transplantation (Allo-BMT), the incidence of relapse is significantly lower in leukemia patients with clinical manifestations of acute or chronic graft versus host disease (GVHD), as compared with patients with no GVHD, indicating that immune-mediated allogeneic interactions of immunocompetent cells of donor origin against the host can be accompanied by graft vs. leukemia (GVL) effects.
Higher relapse rates seem to occur in patients undergoing Allo-BMT with T-lymphocyte depletion for prevention of GVHD, compared to recipients of non-T-cell depleted marrow allografts, regardless of the severity of GVHD. Likewise, relapse rates in patients with acute leukemia or chronic myelogenous leukemia reconstituted by bone marrow grafts obtained from an identical twin (syngeneic grafts) are significantly higher than in those reconstituted by bone marrow cells obtained from an HLA-identical but non-syngeneic sibling. Similarly, relapse rates following transplantation of the patient's own (autologous) marrow, even following adequate purging in vitro for elimination of residual leukemia cells, are significantly higher than following Allo-BMT.
Recent studies by several groups have demonstrated that chronic myelogenous leukemia (CML) patients who relapse following Allo-BMT can be treated successfully by infusion of resting (i.e., unactivated by in vitro treatment with T-cell activators such as cytokines) HLA-matched leukocytes from the Allo-BMT donor in order to achieve a second remission. Slavin et al., Blood 72 (Suppl. 1): 407a (1988); Kolb et al., Blood 76:2462 (1990); Baer et al., J. Clin. Oncology 11:513 (1993); Jiang et al., Bone Marrow Transpl. 11:133 (1993); Drobyski et al., Blood 82:2310 (1993); Antin, Blood 82:2273 (1993); Porter et al., N. Engl. J. Med. 330:100-06 (1994).
The therapeutic effects of the infused leukocytes are mediated by potentiation of GVL effects, induced following Allo-BMT, by immunocompetent donor T cells that are not tolerant to the malignant hematopoietic cells. Slavin et al., Blood 72 (Suppl. 1): 407a (1988); Slavin et al., Bone Marrow Transpl. 6:155-61 (1990); Kolb et al., Blood 76:2462 (1990); Baer et al., J. Clin. Oncology 11:513 (1993); Jiang et al., Bone Marrow Transpl. 11:133 (1993); Drobyski et al., Blood 82:2310 (1993); Antin, Blood 82:2273 (1993); Porter et al., N. Engl. J. Med. 330:100-06 (1994). Unfortunately, only about 50-70% of the CML patients relapsing post Allo-BMT respond favorably to Allo-CT. Kolb et al., Clin. Blood 82 (Suppl. 1):840 (1993). Moreover, long-term disease free survival is far from optimal due to response failures, subsequent relapse and complications arising from GVHD and marrow aplasia.
Finally, the possible anti-solid tumor effects of allogeneic lymphocytes following Allo-BMT have been relatively unknown compared to the documented effects of allogeneic lymphocytes on malignant hematopoietic cells.